Regulatory T cells (Tregs) represent specific subsets of T lymphocytes that are crucial for the maintenance of self-tolerance. These CD4+CD25hi cells with suppressor function can be distinguished from effector T cells by the intracellular expression of the transcription factor Foxp3, as well as other cell markers such as CD127lo, CTLA-4+, LAP, CD39+, PD-1+, GARP, etc. Foxp3 is critical for Treg differentiation and function, and Foxp3 gene deficiency and mutations, both in scurfy mice and patients with immune dysregulation polyendocrinopathy, enteropathy, X-chromosome linked syndrome (IPEX) result in the breakdown of self-tolerance and the development of autoimmune diseases due to Treg deficiency or lack of function.
The autoimmune responses in type 1 diabetes, Systemic Lupus Erythematosus (SLE), multiple sclerosis, and many others are correlated with a deficiency in Tregs. Data from animal models support the hypothesis that autoimmune responses are facilitated by a failure of Tregs to control the destructive immune response to self. Type 1 diabetes is an autoimmune disease that occurs after the destruction of a majority of the insulin producing β cells in the pancreas. The frequency of type 1 diabetes is ˜0.3% of the population in the US and its incidence continues to increase in the US, Europe, and in particular Scandinavia (nearly 1%) and is expected to double within the next twenty years.
The cytokine IL-2 plays a major role in the activation and function of both Tregs as well as effector T cells (Teff). A deficiency in IL-2 production or lack of responsiveness preferentially results in a loss of Treg function and an increase in the probability of autoimmunity. Because Tregs constitutively express the high affinity IL-2 receptor at higher levels than Teff, low doses of IL-2 preferentially support the maintenance of Tregs as compared to Teff cells.
With the preferential effect of IL-2 for activating T s in vitro and in vivo, the potential for low dose, long-lived IL-2 therapy would seem to have a high prospect for success in autoimmune diseases. A 200 patient, double blind, placebo controlled type 1 diabetes clinical trial with IL-2 (Proleukin®) is set to begin in late 2013. Recent clinical trials with daily low dose Proleukin ameliorated some of the signs and symptoms of chronic graft-versus-host disease (GVHD) and hepatitis C virus-induced vasculitis (Koreth et al., New Engl J Med 365, 2055-2066 (2011), Saadoun et al., New Engl J Med 365, 2067-2077 (2011)). In both studies low dose Proleukin induced Tregs and increased the Treg:Teff ratio. However, Proleukin's poor PK properties make it suboptimal for maintaining low, consistent levels of IL-2 in man. Other methods being tested in clinical trials are personalized expansion of Tregs ex vivo followed by reinfusion, but this approach is less than ideal and represents a challenging set of quality control issues.
Thus, a new therapeutic approach that re-establishes the natural regulatory T cell (Treg) mediated dominant immune tolerance would greatly enhance the ability to treat patients with autoimmune diseases such as type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, Crohn's disease as well as other immune-based pro-inflammatory diseases such as chronic graft versus host disease, asthma, pulmonary fibrosis, chronic obstructive pulmonary disease, and transplant rejection, both solid organ and bone marrow.
The IL-2 fusion proteins of the present invention preferentially activate Tregs, tipping the balance toward a higher Treg:Teff ratio and reduce the autoimmune response. They are long-lived, allowing convenient dosing schedules, and devoid of effector functions, reducing potential side effects and impairment of efficacy.